At present, the only treatment for serious insect sting allergies, seasonal allergies and year-round allergies is desensitization (hyposensitization) by an allergist. However, this treatment is expensive, sometimes dangerous, inefficient, painful and frequently ineffective, costing as much as $4,000.00 per year. On average, therapy continues every 2-3 weeks for 3-5 years, resulting in a high dropout rate. In addition, severely sting-allergic individuals must rely on emergency adrenaline and cortisone kits, such as Epipen® (Dey Laboratories, Napa, Calif.), which in many cases are not available at the moment of need. Antihistamines do provide temporary relief from mild allergy symptoms, though often with undesirable side effects and do not prevent anaphylactic shock in severely allergic individuals.
Compositions containing IgG preparations have been used to prevent or control reactions to allergens and antigens. Immune globulin or immunoglobulin are commonly obtained from pooled plasma samples from donors, and typically contains IgG antibodies to various bacterial and viral infectious agents, making it useful for prophylaxis and treatment of disease, particularly in patients with compromised immune systems that make them susceptible to infections. Patients with normal immune systems may also require IgG antibodies in order to overcome certain infections that currently cannot be effectively treated with antibiotics. Many uncommon bacterial infections and viral infections against which patients may have no normal immunity can be treated by administration of immune globulins.
Hyper-immune serum globulin is obtained from plasma from donors selected for high titers (antibody concentrations) of specific antibodies, and has been used to prevent hepatitis B, tetanus, rabies, and varicella-zoster as well as to prevent immunization to the Rh-factor in Rh-negative mothers. Individuals who have recovered from bacterial illnesses typically develop antibodies that can confer immunity in others to the illness. For example, the Rh Immune Globulin (RhoGam®) (Ortho-Clinical Diagnostics, Inc., Raritan, N.J.) has been used to inject into Rh negative mothers to prevent hemolytic disease in their Rh positive fetuses. Also, Medimmune produces Immune Globulin to prevent/treat respiratory syncytial disease virus infections of young children. Immune Globulin preparations such as H-Big™ (NABI) has been used to prevent hepatitis B infection.
In addition, IgG preparations from beekeepers that contain all the IgG subtypes have been used for the treatment of individuals who are sensitive to bee stings (see e.g., Schumacher et al. (1996) Am. J Trop. Med. Hyg. 55(2): 197-201; Lessof et al. (1978) Johns Hopkins Med. J. 142(1): 1-7; and Lessof et al. (1977) Monogr. Allergy 12: 253-256).
Similarly, antitoxins have been shown to be of great value in treating patients envenomated by bacterial toxins or from the bites of venomous snakes or stings of insects. Such antivenins were mostly derived from the serum of immunized horses, but are today almost exclusively obtained from the plasma of immune donors from which the antibody or antibodies are removed. Such antibodies occur in the gamma globulin. A small portion of the population is extremely sensitive (allergic) to the stings of flying insects, especially honey bees, wasps, hornets and yellow jackets (the hymenoptera). The advance of aggressive Africanized or so-called “killer” bees has also increased risks for the general population from multiple bee stings and especially for individuals highly allergic to bee venom. In view of these risks, it is desirable to provide a relatively inexpensive method for manufacturing immune globulins that can provide protection against serious life threatening allergic reactions such as anaphylaxis and/or can be used as an antitoxin to neutralize the toxic properties of the venoms and prevent “end organ” damage, thus possibly saving the life of the victim of the stings. Intravenous administration of immune globulin allows the desired level of circulating antibody to be reached quickly.
Recently, it has been recognized that the IgG4 content is increased in persons exposed to certain allergens. For example, the IgG4 subtype is increased in individuals that have been exposed to bee venom (Aalberse et al. (1983) J. Immunol. 130(2):722-726; Cheung et al. (1983)Ann. Allergy 50(3):155-160; Urbanek et al. (1986) Clin. Allergy16(4):317-322). In many cases, exposure to an antigen or allergen results in an IgG4 restricted response (see, e.g., Aalberse et al. (1983) J. Immunol. 130(2):722-726). For example, exposure to antigens such as grass pollen and honey bee pollen results in IgG antibodies that are predominantly of the IgG4 subclass.
Methods for preparing IgG compositions are known in the art (see, e.g., U.S. Pat. Nos. 6,069,236, 4,719,290, 4,482,483,and 5,177,194). However, no one to date has prepared compositions that comprise IgG4 that is substantially free from other IgG subtypes (e.g., IgG1, IgG2, and IgG3). Such a preparation would have the advantage of containing less protein and a higher amount of blocking antibody (e.g., IgG4) per unit weight or per unit of protein that is being injected. Furthermore, intravenous injections of many immune globulin products can lead to reactions that are caused by aggregation and fragmentation of the immune globulin which forms during the fractionation and preparation of the product. It is desirable, therefore, to provide a method of manufacture of immune globulins that is safe and effective, meeting current standards for sterility and pyrogenicity. Thus, a need in the art exists for IgG4 compositions that are substantially free from other IgG subtypes that can be used in the acute or prophylactic treatment of diseases and conditions. The present invention fulfill these and other needs in the art.